Solid malignancies are generally highly vascularized, and endothelial cells lining the tumor vasculature proliferate faster than endothelial cells of blood vessels in normal tissues. The formation of new blood vessels is called angiogenesis and it involves the migration, growth, and differentiation of endothelial cells. Angiogenesis is an important mechanism for tumor growth, and is believed to be a key to progression of cancer because it provides the necessary supplies of oxygen, nutrients and additional survival factors for the malignant tumors to grow. Because tumors cannot grow beyond a certain size or spread without a blood supply, scientists are trying to find ways to block tumor angiogenesis. Angiogenesis inhibitors interfere with various steps in this process.
Monoclonal antibodies (mAb) recognizing specific tumor-specific vascular proteins can be potential tools for anti-angiogenesis therapy or tumor imaging. They can also deliver therapeutic payloads with high specificity. When endowed with neutralizing properties that can block important vascular cell functions, mAbs can also be administered as “naked” therapy to directly suppress tumor vessel formation and tumor growth. In addition, tagging mAb with imaging tracers or contrast agents allows the parallel development of molecular imaging tools for the same tumor target in vivo. This “theranostics” approach is expected to lead to the development of highly personalized and more effective cancer therapies.
By comparing the vasculature of ovarian cancer and normal ovary a protein called Tumor endothelial marker 1 (TEM1 or endosialin, CD248) has been identified, which is highly expressed on the tumor vessels but not on the vessels in the normal, healthy tissue. TEM1 is an 80.9 kDa cell surface protein implicated in the development, vascular cell adhesion and migration and tumor progression. TEM1 has also been found in the vasculature of breast, colon cancer, sarcomas, brain and other tumors. These data suggest TEM1 is a valuable marker for imaging tumor vasculature and for development of effective cancer therapeutics. A high-affinity single chain antibody clone against TEM1 (isolated from a large yeast display library), scFv78, described in U.S. application publication No. US2012/0294799, which is incorporated herein by reference in its entirety, specifically recognizes the murine and human TEM1 protein. However, there remains a need in the art for anti-TEM1 antibodies and antigen-binding fragments, with high stability in serum and/or high affinity for TEM1.